This research proposal explores the possibility that the mesangial lesions of diabetic glomerulosclerosis may result in part from the nephrotoxic effects of abnormally glycosylated macromolecules taken up by the glomerular mesangium. Abnormally glycosylated proteins are currently being incriminated in diabetic lesions in other tissues. That similar materials could also contribute to the production of mesangial lesions is suggested by the experimental finding that certain carbohydrate macromolecules accumulate in the mesangium and cause focal changes there including impairment of mesangial catabolic function similar to that demonstrable in diabetic nephropathy. Thus, persistence in the mesangium of material able to cause further damage would allow initial foci to accumulate more, leading to segmental, nodular lesions of Kimmelstiel-Wilson type. The hypothesis will be tested in experimental animals (a) by analyzing the lesions produced by diabetes and by carbohydrate polymers; (b) by accurately quantitating whether glycosylated macromolecules derived from diabetics localize more or persist longer in the normal glomerular mesangium than comparable normal macromolecules; and (c) by determining whether the carbohydrate content of repeatedly injected macromolecules is a determinant of glomerular toxicity. These studies will capitalize on methods developed for the histologic and kinetic study of the handling of radioiodinated aggregates localizing within the glomerulus. The long term goals of this work include the further understanding of the pathogenesis of diabetic glomerulosclerosis and the identification of mechanisms of disease that may potentially point the way to new methods of preventing or intervening in the development of some aspects of diabetic renal disease.